Test Summary
Spinal Muscular Atrophy (SMA) Carrier Screen
Test Code: 39445
Clinical use
- Screen for carriers of spinal muscular atrophy (SMA)
- Assess risk of having a child with SMA
Clinical background
SMA is an autosomal recessive disease that causes progressive muscle wasting and weakness due to loss of motor neurons in the spinal cord and motor nuclei in the brainstem. SMA is a leading genetic cause of death in infants, with an incidence of approximately 1 in 10,000 live births.1 Disease-modifying therapies are now available and provide the most benefit when administered early.1
Because of the severity and high incidence of SMA, the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) recommend population-based carrier screening before conception or during pregnancy.2,3 Carrier screening allows planning for prenatal diagnosis and prompt treatment of an affected child.
SMA involves 2 homologous survival motor neuron (SMN) genes on chromosome 5: SMN1 and SMN2. Approximately 95% of SMA cases are caused by homozygous deletion of SMN1 exon 7; the remaining cases typically involve other alterations in SMN1.2,3 Alterations in SMN2 do not cause disease, but increased SMN2 copy number is associated with attenuated severity of SMA.1 Gene dosage analysis of SMN1 exon 7 is performed to identify SMA carriers,3–5 whereas analysis of SMN2 may help predict clinical severity in an affected child.
Most carriers have a gene dosage of 1 copy of SMN1:1 intact copy of SMN1 on 1 copy of chromosome 5 and a partially deleted (ie, abnormal) copy of SMN1 on the other copy of chromosome 5.1,2 However, some carriers have screening results that show a gene dosage of 2 copies, a result expected from noncarriers. This result can be caused by a duplication of intact SMN1 on 1 copy of chromosome 5 and a deleted (abnormal) copy of SMN1 on the other copy of the chromosome.2
These “silent carriers” have historically been missed, but a variant in SMN1 (g.27134 T>G [rs143838139]) that modifies risk for this duplication has been identified.6 Although linkage of the g.27134 T>G variant with SMN1 duplication varies by ethnicity, testing for the variant in combination with SMN1 copy number increases overall detection of SMA carriers.7 Accordingly, ACMG technical guidelines state that testing for this variant in individuals with 2 copies of SMN1 improves estimates of risk for SMA carrier status.5,8
The Spinal Muscular Atrophy (SMA) Carrier Screen first assesses SMN1 exon 7 copy number. If the individual has 0 or 1 copy of SMN1, then SMN2 copy number is assessed to help predict clinical severity in an affected child. If 2 copies of SMN1 are detected, then testing for the g.27134 T>G variant is performed to assess risk of being a silent carrier; if the g.27134 T>G variant is detected, then SMN2 copy number is also assessed.
Individuals suitable for testing
- Individuals who are pregnant or considering pregnancy
- Partners of individuals who have been identified as carriers for SMA
- Individuals with a family history of SMA
Method
- Quantitative PCR to assess SMN1 exon 7 copy number and, when indicated, presence of the g.27134 T>G variant and/or SMN2 copy number
Interpretive information
Detection of 0 copies of SMN1 is consistent with a diagnosis of SMA.
Detection of 1 copy of SMN1 is consistent with being a carrier for SMA.
If 2 copies of SMN1 are detected and the g.27134 T>G variant is present, the individual is more likely to be a carrier, with the magnitude of the residual risk dependent on their ethnicity (Table).
When both partners are carriers, the chance of having a child with SMA is 1 in 4 (25%).
A small percentage of carriers have other (non-deletional) pathogenic variants that are not detected with this test. Thus, genetic counseling should include discussion of residual risk for being an SMA carrier when 2 copies of SMN1 are detected.
Table. Estimated SMA Carrier Detection Rate and Carrier Risk by Ethnicity
Ethnicity7 |
Population carrier risk |
Carrier detection ratea |
Residual risk/variant absentb |
Residual risk/ variant presentc |
Caucasian |
1:47 |
95% |
1:921 |
1:69 |
Ashkenazi Jewish |
1:67 |
93% |
1:918 |
Likely carrier |
Asian |
1:59 |
94% |
1:907 |
1:61 |
African American |
1:72 |
90% |
1:375 |
1:39 |
Hispanic |
1:68 |
93% |
1:906 |
1:99 |
| SMA, spinal muscular atrophy. | |
| a | Percentage of SMA carriers identified using SMN1 copy-number analysis and SMN1 g.27134 T>G variant analysis. |
| b | Residual risk of being an SMA carrier after a screening result of 2 copies of SMN1 and negative for the g.27134 T>G variant. |
| c | Residual risk of being an SMA carrier after a screening result of 2 copies of SMN1 and positive for the g.27134 T>G variant. |
Additional assistance in interpretation of results is available from our Genomic Science Specialists by calling Quest Genomic Client Services at 1.866.GENEINFO (1.866.436.3463).
References
- Keinath MC, Prior DE, Prior TW. Spinal muscular atrophy: mutations, testing, and clinical relevance. Appl Clin Genet. 2021;14:11-25. doi:10.2147/tacg.s239603
- American College of Obstetricians and Gynecologists’ Committee on Genetics. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55. doi:10.1097/aog.0000000000001952
- Prior TW; Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med. 2008;10(11):840-842. doi:10.1097/gim.0b013e318188d069
- Prior TW, Nagan N, Sugarman EA, et al. Technical standards and guidelines for spinal muscular atrophy testing. Genet Med. 2011;13(7):686-694. doi:10.1097/gim.0b013e318220d523
- Deignan JL, Astbury C, Behlmann A, et al. Addendum: Technical standards and guidelines for spinal muscular atrophy testing. Genet Med. 2021;23(12):2462. doi:10.1038/s41436-020-00961-6
- Luo M, Liu L, Peter I, et al. An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy. Genet Med. 2014;16(2):149-156. doi:10.1038/gim.2013.84
- Feng Y, Ge X, Meng L, et al. The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing. Genet Med. 2017;19(8):936-944. doi:10.1038/gim.2016.215
- Addendum: Technical standards and guidelines for spinal muscular atrophy testing. Genet Med. 2016;18(7):752. doi:10.1038/gim.2016.76
Content reviewed 4/2025
39445 - Spinal Muscular Atrophy (SMA) Carrier Screen
Reference ranges are provided as general guidance only. To interpret test results use the reference range in the laboratory report.
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